Peroxisomal Enzyme Deficiencies in Rhizomelic Chondrodysplasia Punctata: Biochemistry and Therapeutic Avenues

Background - Peroxisomes are organelles of our cells where they perform a variety of functions, especially in the metabolism of fatty acids and membrane phospholipids. Among the peroxisomal functions, there is the generation of a group of phospholipid molecules that are essential for cell membranes; the plasmalogens. Deficiencies in plasmalogen biosynthesis cause Rhizomelic Chondrodysplasia Punctata (RCDP), a genetic disease with very severe clinical manifestations including skeletal malformations and growth and mental retardations. As for most peroxisomal disorders, also for RCDP there is essentially no available specific therapy. On the other hand, thanks to the improvement in medical care, RCDP patients can live even up to 10 years so that progress in diagnosis and treatment is greatly needed to support patients and improve their life conditions. Results - Our project followed the logic of "knowledge for action". Thanks to Telethon support, we have demonstrated that the RCDP-causing mutations fully inactive the generation of the plasmalogens. Thus, this is essentially a disease triggered by the deficiency of essential components in the cells of our body. A second important result is that our research led to the discovery of fully unexpected properties of the peroxisomal components that produce the plasmalogens. These findings now allow us to rationalize the specific clinical characteristics of the disease. A third fundamental outcome is the ingenious development (by the two youngest members of our team) of essential tools, now finally in the hands of researchers, to fully understand the physiological roles of the plasmalogen cell components. Perspectives - RCDP is shown to be a disease that drastically impair the generation of essential molecules for our cells. In addition to supporting improved diagnosis, the knowledge gained from our studies is the essential initial step towards therapeutic approaches, which include gene therapy and synthetic enzyme supplementation as long-term goals.